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(MRC DTP) Developing a zebrafish model for a novel human neurodevelopmental disorder

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  • Full or part time
    Prof G D Pavitt
    Dr P Kasher
    Dr S Banka
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

Background
We have recently discovered a novel human disorder caused by mutations in the EIF5A1 gene resulting in developmental problems, small head size and craniofacial defects in children [1]. EIF5A1 is unique because it is the only known protein to contain the amino acid hypusine and is essential for proper synthesis of a set of important proteins[2]. Using yeast and zebrafish model systems we have shown how EIF5A1 mutations lead to impaired eIF5A function and cause phenotypes consistent with the disease. Interestingly, in the same model systems we have shown that a specific food supplement may be a potential treatment for this disease[1].
Project
The normal expression pattern of eIF5A1 in developing zebrafish will be studied using in-situ hybridisation and fluorescent microscopy. CRISPR/Cas will be used to generate zebrafish lines with human EIF5A1 mutations. These fish will be characterized for brain and craniofacial defects and their tissues will be studied using Mass-spectrometry, RNA-seq and biochemical assays of eIF5A functions. Phenotype rescue studies of the mutant zebrafish will be performed. An international patient registry will be developed for further studying the human phenotype and to prepare a cohort for future treatment trials.
Outcome
The student will generate and characterise vertebrate models of a novel human disorder at the interface of fundamental biology and translational precision medicine. The student will learn several fundamental interdisciplinary and quantitative skills, as well as gaining significant experience of studying whole organism physiology in context of human disease.

https://www.research.manchester.ac.uk/portal/graham.pavitt.html
https://www.research.manchester.ac.uk/portal/paul.kasher.html
https://www.research.manchester.ac.uk/portal/siddharth.banka.html

Entry Requirements:
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the MRC DTP website www.manchester.ac.uk/mrcdtpstudentships

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

1. V Faundes, MD Jennings, S Legraie, S Crilly, S Cuvertino, SJ Davies, A Douglas, A Fry, V Harrison, J Amiel, D Lehalle, WG Newman, P Newkirk, J Ranells, M Splitt, CT Gordon, PR Kasher, GD Pavitt, S Banka. Impaired eIF5A function associated with a novel neurodevelopmental disorder is rescued in model systems by spermidine. In preparation.
2. Gutierrez, E. et al. eIF5A promotes translation of polyproline motifs. Mol Cell 51, 35-45 (2013)



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